Retracted stem cell papers get public, private scrutiny

Researcher Haruko Obokata (right) bowed in apology with her lawyer at a press conference in Osaka, Japan. A top scientific institute in Japan found errors in data in stem cell research by a group of scientists, including its own.EPA

This is a tale of two stem cell research papers.

One took the scientific world aback when it appeared in late January: a report by a team of Boston and Japanese researchers that stem cells could be created simply by dipping mature cells in an acid bath.

The second was less splashy, but also surprising. A 2012 paper described how the heart naturally replenishes itself; it reported a rate of renewal of heart muscle cells that was dramatically higher than other researchers had found. The work, led by a prominent Brigham and Women’s Hospital researcher, also showed that the rate of cell regeneration increased as people got older -- contrary to expectations.

Something would turn out to be wrong with both papers. Where these two tales diverge is how these problems have been handled.

In the weeks since the paper describing the acid bath technique was published in the journal Nature, it has been thoroughly -- and publicly -- picked apart. Several of its Japanese authors have held press conferences. The president of the RIKEN research institution in Tokyo, where many of the authors work, has apologized to the scientific community, prefacing his public remarks with a deep bow. RIKEN has released detailed reports and been specific about what portions of the paper it was investigating and what was found. It publicly accused a young scientist named Haruko Obokata of fraud, a finding she is appealing.

The incident has sparked a national discussion about the state of science in Japan and the need to ensure high standards in order not to lose the world’s trust.

In contrast, the 2012 paper was withdrawn in April without fanfare: a barebones retraction notice posted by the journal Circulation stated an institutional review had found that the paper contains unspecified “compromised” data. No details were provided about what was wrong with the data.

The finding came from the laboratory of Dr. Piero Anversa, a pioneer in heart stem cells at Harvard Medical School and the Brigham. The chief science officer of the American Heart Association, which publishes the journal, said Harvard had informed the association that problems existed in multiple figures in the paper, but did not specify what the issues were. In a March 25 letter to the editor of the Lancet, where a second paper from Anversa has been flagged due to concerns about the integrity of some of the data, a Harvard Medical School dean told the journal an ongoing investigation would take several more months.

The Brigham has declined to provide more information about the investigations or the nature of the problems that caused the retraction.

“Any questions, concerns or allegations regarding research conducted at BWH are confidentially evaluated per the hospital’s policies and federal regulations,” the hospital said in a statement. “Beyond that, it is not appropriate for BWH to comment on these matters further at this time.”

Investigations into research problems are typically confidential in the United States. Nicholas Steneck, director of the research ethics program at the University of Michigan Institute for Clinical and Health Research, said there is a strong emphasis here on protecting the privacy and identity of people until a review is concluded.

Other countries might handle investigations differently because they fear for their national scientific standing. “They are very, very concerned about being tainted by misconduct and that’s why they take this very public,” Steneck said. “In the U.S. ... we don’t worry about it undermining our national reputation. Is Harvard worried about losing its reputation as a top research institution in the U.S.?”

Paul Knoepfler, a stem cell scientist at the University of California Davis School of Medicine who has blogged extensively about the acid-bath study, said he has mixed feelings about how the investigation has unfolded.

“In theory, a speedy, relatively open investigation could be in the best interest of science and the parties involved in any given controversial situation, but it must be balanced with the need for thoroughness and fairness,” he wrote in an e-mail.

The Japanese scientist who led that work is still vouching for the integrity of the finding, despite the errors in the paper. So is the Brigham scientist who oversaw the work, Dr. Charles Vacanti. But the very public investigation and revelation of problems with the paper have led to disclosure of specific flaws, and Japanese scientists have said they are now trying to demonstrate whether the overall finding holds up.

The disclosure of so few details about the nature of the problems with the heart stem cell study has left other scientists unsure of how serious or widespread the issues might be -- and what to make of Anversa’s other work, which extends to more than 350 scientific publications, some of which have been critiqued by outside scientists in the past.

Anversa himself has said by e-mail that he can’t expand further on what the problems were due to the ongoing investigation, but that he believes the conclusions in both of the papers under scrutiny are true.

When a university has taken an action, such as withdrawing a paper or notifying a journal of concerns, “that’s a public act, and you have some obligation to explain the basis of that public act,” Steneck said. “Because in many of these cases, what you will see is only a portion of the data is actually compromised, and this is precisely what other researchers need to know.”

Dr. Joshua Hare, the guest editor for the retracted paper, said that he found it unusual that he was not alerted by the scientists or the American Heart Association that the paper would be withdrawn.

“There’s no specific reference to what was wrong with the paper,” Hare said. “I think the field demands that we know what’s wrong with the paper. This field is of fundamental importance to the health of human beings right now.”

Even co-authors do not know precisely what is wrong. Dr. Roberto Bolli at the University of Louisville was the lead author of the Lancet paper that has been flagged as having possible problems with the integrity of data produced in Boston. Bolli ran the clinical trial using cells prepared by Anversa’s laboratory and said the results of the paper are solid and the problems have nothing to do with work done at Louisville.

“I am anxious to find out the results of the investigation and hope that the committee will shed full light into this issue,” Bolli wrote in an e-mail.